I am committed to engaging in clinically relevant basic science research and my long-term goal is to become an independent investigator dedicated to understanding the pathophysiology of autoimmune disease. Under the mentorship of Dr. Mathis and Dr. Brenner, I will develop an independent research program within the time frame of this award. My prior training in clinical medicine and immunology will provide me with the necessary background to pursue the project proposed in this application, which is positioned at the interface of basic science and disease-focused research. The experiments outlined in the Specific Aims focus on the role of IL-1 in a prototypical autoimmune disease, inflammatory arthritis. IL-1 is a critical mediator of inflammation, acting at the intersection of the innate and adaptive arms of the immune response. IL-1 has been implicated in the pathogenesis of many autoimmune and infectious diseases. The host lab has recently shown in a murine system that variation in the gene encoding IL-1 beta, Il1b, alters the level of expression of IL-1 alpha and IL-1 beta as well as susceptibility to a model of inflammatory arthritis. My preliminary data show that a locus on chromosome 19 can also influence the level of IL-1 alpha RNA expression. In Aim 1, I propose to identify the gene on chromosome 19 that alters the level of IL-1 alpha RNA expression. This gene might also affect susceptibility to inflammatory arthritis and could offer a new target for further study. In Aim 2, I propose to examine the biologic role of IL-1 in the mouse model of inflammatory arthritis in order to gain a more complete understanding of disease pathogenesis. The proposed project is relevant for the study of inflammatory arthritis. In addition, given the pleiotropic effects of IL-1 in inflammation, the results can be broadly applied to other disease states including other autoimmune conditions, infection, and cancer.